The objective of the proposed research is to develop methods to increase (or decrease) the rate of ethanol metabolism for the treatment of acute and chronic alcoholism. Since liver alcohol dehydrogenase catalyzes a rate-limiting step in the removal of alcohol from the blood, we propose to develop active-site-directed reagents that will increase (or decrease) the activity of the enzyme in vivo. Ethanol metabolism could be accelerated by the use of an oxidizing agent that reacts with the alcohol dehydrogenase-NADH complex to regenerate NAD ion. Compounds that could participate in this coupled reaction with appropriate kinetic and pharmacological characteristics will be sought. Modification of one amino group per active site of the horse liver enzyme increases the activity in vitro up to 10-times; the human enzyme can also be activated. The role of the amino group in the mechanism of activation of the enzyme will be defined by kinetic, chemical and X-ray crystallographic studies. With knowledge of the location of the amino group in the active site, reagents will be made that should specifically modify the amino group and activate the enzyme. Ethanol metabolism could be inhibited by compounds that inhibit or inactivate alcohol dehydrogenase. Chemical modification of cysteine or methionine residues in the active site of the dehydrogenase inactivates the enzyme. Reagents for the specific modification of these residues will be designed, synthesized, and evaluated in vitro and in vivo. Reagents that specifically activate (or inactivate) the enzyme in vivo, that are not too toxic and that meet other pharmacological criteria could be used eventually for therapy. They would also be valuable for studying the metabolism and toxicology of ethanol.